Asymmetric epoxidation reaction

ABSTRACT

A process for producing an optically active benzopyran compound of the formula [I] or [II]: ##STR1## in which an olefin compound of the formula [V] or [VI]: ##STR2## is subjected to asymmetric epoxidation reaction, using, as a catalyst, an optically active manganese complex of the formula [III] or [IV]: ##STR3##

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a benzopyran compound, which is animportant intermediate in synthesis of optically activepyranobenzoxadiazole compounds useful for the treatment of hypertension,asthma, etc., and to a process for producing the same.

2. Description of the Prior Art

Pyranobenzoxadiazole compounds of the formula [VII ]: ##STR4## wherein Arepresents a hydroxyl group or OC(O)CH_(3-n) X_(n), in which X isfluorine atom, chlorine atom, bromine atom, methyl group or methoxygroup and n is 0 or an integer of 1 to 3;

when R^(a) represents a hydrogen atom, R^(b) represents a hydrogen atom,C(Z)CH_(3-n) X_(n) or C(Z)NHCH_(3-n) X_(n) in which Z represents oxygenatom or sulfur atom and n has the same meaning as defined above; and

when R^(a) does not represent a hydrogen atom, R^(a) and R^(b) togetherform (CH₂)_(m-1) C(Z) in which m is an integer of 4 or 5 and Z has thesame meaning as defined above, (CH₂)_(m-2) NHC(Z) or (CH₂)_(m-2) OC(Z)in which Z and m have the same meanings as defined above, are describedin Japanese Patent Laid-Open No. Hei 2-49788 (49788/1990), EP-A-0 327127 and U.S. Pat. No. 4,900,752. The compounds exert intensevasodilatory and hypotensive activities, and thus are expected to beuseful as a medicine for treating hypertension, angina pectoris,arrhythmia, cerebral circulation disorder and asthma.

There are two kinds of optical isomers for the compounds of the formula[VII]since the compounds have asymmetric carbon atoms at the 3- and4-positions of the pyran ring, and only one antipode exhibits excellentactivity as a medicine, as shown in Japanese Patent Laid-Open No. Hei3-141286 (141286/1991) , EP-A-0 409 165 and U.S. Pat. No. 5,097,037.However, since the antipode is synthesized from an optically activecompound [VIII] (an optically active compound showing dextrorotation inethanol) as a raw material in accordance with Scheme 1. The productionthereof has shown economical problems. (see Japanese Patent Laid-OpenNo. Hei 3-141286, EP-A-0 409 165 and U.S. Pat. No. 5,097,037). ##STR5##

SUMMARY OF THE INVENTION

Thus, the present invention is to establish a process for producingoptically active pyranobenzoxadiazole compounds [VIII] in an effectiveand economical manner, wherein optically active isomers of Compound [I]:##STR6## in which R represents hydrogen atom or an amino-protectinggroup and the absolute configuration of carbon atom which is marked withasterisks means R or S or optically active isomers of Compound [II]:##STR7## in which n is 0 or an integer of 1 and the absoluteconfiguration of carbon atom means R or S, are synthesized in anenantioselective manner by utilizing asymmetric synthesis.

An object of the present invention is to provide a process for producingan intermediate compound of a therapy of hypertension.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present inventors extensively investigated asymmetric epoxidationreaction (Reaction 1 and Reaction 2 as shown below) of olefin compounds[V]: ##STR8## in which R represents hydrogen atom or an amino-protectinggroup or olefin compounds [VI]: ##STR9## in which n is 0 or an integerof 1 so as to obtain the optically active benzopyran compounds [I]:##STR10## in which R has the same meaning as defined above and theabsolute configuration of carbon atom which is marked with asterisksmeans R or S or optically active benzopyran compounds [II]: ##STR11## inwhich n is 0 or an integer of 1 and the absolute configuration of carbonatom which is marked with asterisks means R or S. As a result, theyfound out that the intended compounds can be obtained at the highestasymmetric yields by using, as asymmetric catalyst, an optically activemanganese complex of the formula [III] wherein R¹, R², R³, R⁴ and R⁵ canbe same or different and represent hydrogen atom or straight chain orbranched alkyl group having 1 to 4 carbon atoms, or phenyl group whichis unsubstituted or substituted by one or more substituents arbitrarilyselected from one or more groups of fluorine atom, chlorine atom,bromine atom, straight chain or branched alkyl group having 1 to 4carbon atoms and straight chain or branched alkoxyl group having 1 to 4carbon atoms, R⁶ represents straight chain or branched alkyl grouphaving 1 to 4 carbon with proviso that when R⁶ represents ethyl group,either one of R¹ and R² and either one of R³ and R⁴ do notsimultaneously represent phenyl group, Ar represents phenyl group whichis unsubstituted or substituted by one or more substituents arbitrarilyselected from one or more groups of fluorine atom, chlorine atom,bromine atom, straight chain or branched alkyl group having 1 to 4carbon atoms and straight chain or branched alkoxyl group having 1 to 4carbon atoms, and the absolute configuration shown by the asterisksmeans R or S and X⁻ represents a counter anion or an optically activemanganese complex of the formula [IV ] wherein R¹, R², R³, R⁴, R⁵, X⁻and the asterisks are defined above. ##STR12##

R which is a substituent of the compound [I] represents hydrogen atom oran amino-protecting group. Examples of the protecting group include acylgroup such as acetyl group, propionyl group, benzoyl group,alkoxycarbonyl group such as methoxycarbonyl group, ethoxycarbonyl groupand tertiary butoxycarbonyl group, and tosyl group and benzyl group.Preferable examples of R are acetyl group and tertiary butoxycarbonylgroup.

The olefin compound [V] as a starting material is known and can bereadily synthesized according to the methods described in JapanesePatent Laid-Open No. Sho 52-91866 (91866/1977) and British Patents No.1,548,221 and No. 1,548,222. The olefin compound [VI] can be readilysynthesized according to the methods described in Japanese PatentLaid-open No. Hei 2-49788 (49788/1990), EP-A-0 327 127 and U.S. Pat. No.4,900,752, by using the compound [V] as a starting material.

Examples of R¹, R², R³, R⁴ and R⁵ which are substituents of theoptically active manganese complexes [III] and [IV] include hydrogenatom, methyl group, ethyl group or straight chain or branched alkylgroup having 3 to 4 carbon atoms such as normal-propyl group, isopropylgroup, normal-butyl group, isobutyl group, secondary butyl group andtertiary butyl group, or phenyl group which is unsubstituted orsubstituted by one or more substituents arbitrarily selected from one ormore groups of fluorine atom, chlorine atom, bromine atom, methyl group,ethyl group, normal-propyl group, isopropyl group, normal-butyl group,isobutyl group, secondary butyl group and tertiary butyl group, methoxygroup, ethoxy group, normal-propoxy group, isopropoxy group, normal-butoxy group, isobutoxy group, secondary butoxy group and tertiarybutoxy group, preferably, hydrogen atom, ethyl group and phenyl group.

Examples of R⁶ include methyl group, ethyl group, normal-propyl group,isopropyl group, normal-butyl group, isobutyl group, secondary butylgroup and tertiary butyl group, preferably, methyl group and ethylgroup.

Examples of Ar include fluorine atom, chlorine atom, bromine a tom,methyl group, ethyl group, phenyl group which is unsubstituted orsubstituted by one or more substituents arbitrarily selected from one ormore groups of normal-propyl group, isopropyl group, normal-butyl group,isobutyl group, secondary butyl group and tertiary butyl group, methoxygroup, ethoxy group, normal -propoxy group, isopropoxy group, normalbutoxy group, isobutoxy group, secondary butoxy group, tertiary butoxygroup; preferably, phenyl group.

The optically active manganese complexes [III] and [IV] can form salttogether with various kinds of counter anion (X⁻) as manganese which isa metal center can be monovalent to pentavalent oxidized state. Examplesof the counter anion include monovalent OH⁻, F⁻, Cl⁻, Br⁻, I⁻, CH₃ CO₂⁻, PF₆ ⁻ and ClO₄ ⁻ ions, divalent CO₃ ²⁻ and SO₄ ²⁻, trivalent PO₄ ³⁻ion. All of these salts can be used as asymmetric catalyst of thepresent invention.

The following is the typical synthesis examples of the optically activemanganese complexes [III] and [IV].

The Scheme 2 shows a case of the complex of the formula [III] wherein R¹=R² =H, R³ =R⁴ =R⁵ =R⁶ =CH₃ and Ar=Ph (phenyl group). Namely, 4 -methyl-salicylic acid is (a) esterificated with methyl orthoformate and thensubjected to (b) cinnamylation under basic conditions, (c) Claisenrearrangement in the presence of calcium carbonate, (d) catalyticreduction and then to (e) hydrolysis of ester to give a racemiccarboxylic acid. Subsequently, the racetalc carboxylic acid is (f)optically separated by using brucine as an optically resolving agent,(g) reacted with lithium aluminum hydride (LAH) to reduce the carboxylicgroup of the acid into an alcohol, and then (h) oxidized the alcoholwith 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) to give opticallyactive 4-methyl-3-(1-phenylpropyl )salicylaldehyde, which can beconverted into the optically active compound [III] in accordance withthe method described in Example 1 or 2 (see Tetrahedron Letters , Vol.32, No. 8 , 1055-1058 (1991)). In the method described in Examples 1 or2, the above-mentioned aldehyde is stirred in ethanol together withmanganese acetate-tetrahydrate and then reacted with1,2-diamino-2-methylpropane. After distilling off the solvent, theresidue is recrystallized from hexane-acetone to obtain the desiredproduct. ##STR13##

The Scheme 3 shows a case of the complex of the formula [III] wherein R⁶=CH₃ and Ar=Ph Namely, 2-hydroxyacetophenone which is substituted withR⁵ is (a) alkylated by phenyllithium in the presence of cerium chlorideand is (b) hydrogenerated by Pd-C under the acidic conditions, and (c)under acidic conditions , tetrahydropyranyl group (THP) is introducedand (d) formyl group is introduced via ortholithiation andtetrahydropyranyl group is (e) deprotected under acidic conditions, andthe obtained salicylaldehyde derivative is (f) reacted with(-)-methylchloroformate and the obtained diastereomer is separated byrecrystallization. Then, (g) by hydrolyzing methylcarbonate by alkali,the optically active 3- (1-phenylethyl)-salicylaldehyde substituted withR⁵ is prepared. In accordance with the method described in Example 2,the optically active compound [III] is prepared from thesalicylaldehyde. ##STR14##

An optically active (salen)manganese complex [IV] can be synthesized bythe routes shown in the Scheme 4 . Namely, (a) Phenol substituted withR⁵ is reacted with 3-chloropropionic acid chloride to obtain ester, (b)the Fries rearrangement and Friedel Crafts alkylation are simultaneouslyconducted by A1C13, (c) alkylation is made by phenylmagnesium bromide,(d) hydroxyindane derivative obtained by Pd-C hydrogenation under basicconditions is (e) reacted with (-)-methylchloroformate to obtaindiastereomer. The diastereomer is separated by recrystallization. Then,(f) menthylcarbonate is alkalihydrolyzed and (g) under acidicconditions, phenol is protected as tetrahydropyrane. After (h) formylgroup is introduced via ortholithiation, (i) tetrahydropyranyl group isdeprotected under basic conditions to prepare an optically active6-formyl-7-hydroxy-1-phenylindane substituted with R⁵. In accordancewith the method described in Example 3, the optically active compound[IV ] can be obtained from the phenylindane. ##STR15##

Next, the method (Reaction Scheme 1 or 2) for preparing optically activebenzopyrane compound [I] or [II ] is explained.

Asymmetrical catalyst, namely, optically active manganese complex [III]or [IV ], is used at a concentration in the range of from 0.1 mol % to100 mol %, preferably from 1 mol % to 5 mol %, based on the mole of thecompound of the formula [V] or VII. Examples of usable oxidizing agentsinclude iodosobenzene, sodium hypochlorite, and the like. Wheniodosobenzene is used as the oxidizing agents, it is usually used in therange of from 1 to 10 equivalents, preferably 1 to 3 equivalents, basedon the compound [V] or [VI]. When sodium hypochlorite is used as theoxidizing agents, it is usually used in the range of from 1 to 100equivalents, preferably, in the range of from 3 to 30 equivalents.

As a medium for the reaction, there can be used water, acetonitrile,dichloromethane, dichloroethane and a mixture thereof. Especially, whensodium hypochlorite is used as the oxidizing agent, it may be preferableto use two-phase system such as water and dichloromethane. Also, it canco-exist a component having coordination ability with the manganesecomplex such as pyridine N-oxide, lutidine N-oxide or 2-methylimidazolein the reaction system. There is no particular limitation on thequantity of the components to be used.

The reaction is ordinarily carried out at a temperature in the range of-20° C. to 50° C., preferably, -20° C. to 25° C.

After the completion of the reaction, the organic solvent is distilledoff under reduced pressure to concentrate the reaction solution and onlyseparated and purified by using a silica gel column chromatography toisolate the desired optically active compound [I] or [II]. The opticalpurity of [I] or [II] can be analyzed by optically active liquidchromatographic column (using, e.g., Chiralcel OJ mfd. by DaicelChemical Industries, Ltd., under conditions as shown in Example).

The present invention will further be illustrated by examples.

EXAMPLES

Example 1

Synthesis of Optically Active Manganese Complex [III (R¹ =R² =H, R³ =R⁴=R⁵ =CH₃, R⁶ =CH₂ CH₃ and Ar=Ph)]

(1) R-isomer (catalyst A) ##STR16##

To 2.8 ml of ethanol were added 97.0 mg (0.381 mmol) of (R)-4-methyl-3-(1-phenylpropyl)salicylaldehyde (a compound known to the literature,Tetrahedron Letters , Vol. 32 , No. 8, 1055-1058 (1991)) and 47.1 mg(0.192 mmol) of manganese acetatetetrahydrate, and the resulting mixturewas stirred for twenty minutes. Subsequently, 20 μl (0.193 mmol ) of1,2-diamino-2-methylpropane was added thereto, and the resulting mixturewas stirred for twenty hours.

Thereafter, the reaction mixture was concentrated under reducedpressure, and the residue obtained was recrystallized fromhexane-acetone to obtain 77.5 mg (yield=56%) of the titled compound(catalyst A).

IR: 2956, 1615, 1585, 1525, 1381, 1291, 745, 694, 639 cm⁻¹

Elementary Analysis:

Calcd. for C₄₀ H₄₅ Mn₁ N₂ O₄.AcOH: C, 68.84; H, 6.73; N, 3.82 Found: C,68.62; H, 6.59; N, 3.81

(2) S-isomer

The titled compound was synthesized in a similar manner described above,by using (S)-4-methyl-3-(1-phenylpropyl)salcylaldehyde as a startingmaterial. IR: 2956, 1615, 1585, 1525, 1381, 1291, 745, 694, 639 cm⁻¹

Example 2

Synthesis of Optically Active Manganese Complex [III (R¹ =R³ =H, R² =R⁴=Ph, R⁵ =R⁶ =CH₃ and Ar=Ph)]

(1) R-isomer (catalyst B)

To 0.36 ml of degassed acetonitrile (dried on MS4A) were added 43.3 mg(0.180 mmol) of (R)-4-methyl-3-(1-phenylethyl) salicylaldehyde and 19.2mg (0.090 mmol) of (R, R)-1,2-diphenylethylenediamine and stirred fortwenty minutes. The mixture was added with 0.36 ml of solution of 22.1mg (0.090 of manganese acetate-tetrahydrate in acetonitrile and stirredfor four hours. To the mixture was poured 0.36 ml of solution of 29.9 mg(0.090 mmol) of ferricenium hexafluorophosphate (Cp₂ FePF₆) inacetonitrile and was stirred for fifteen hours. Thereafter, the residueobtained by concentration under reduced pressure was washed thrice with2 ml of hexane to obtain the titled compound (catalyst B). (yield: 54%)

(2) S-isomer (catalyst C)

The titled compound (catalyst C) was obtained in the similar mannerdescribed above by using (S,S)-1,2-diphenylethylenediamine instead of(R,R)-1,2-diphenylethylenediamine.

Example 3

Synthesis of Optically Active Manganese Complex [IV (R^(d1) =R³ =H, R²=R⁴ =Ph, R⁵ =H and Ar=Ph)]

(1) R-isomer (catalyst D)

To 0. 6 ml of ethanol were added 45.3 mg (0.190 mmol) of(R)-6-formyl-7-hydroxy-1-phenylindane and 23.3 mg (0,095 mmol) ofmanganese acetate-tetrahydrate and stired for twenty minutes. Themixture was added 20.2 mg (0.095 mmol) of(R,R)-1,2-diphenylethylenediamine and further stirred for twenty hours.Thereafter, the residue obtained by concentration under reduced pressurewas recrystallized from hexane-dichloromethane to obtain the titledcompound (catalyst D). (yield: 43%)

(2) S-isomer (catalyst E)

The titled compound (catalyst E) was obtained in the similar mannerdescribed above by using (S,S)-1,2-diphenylethylenediamine instead of(R,R)-1,2-diphenylethylenediamine.

Example 4 (Asymmetric Epoxidation Reaction)

(1) Reaction Example which uses iodosobenzene as an oxidizing agent

To 1.4 ml of acetonitrile were added 0. 068 mmol of the compound [V] or[VI], 1.36×10⁻³ mmol of the optically active (salen)manganese complex[III] or [IV] and 0.136 mmol of iodosobenzene and stirred for twentyfour hours at room temperature or -20° C. After the completion of thereaction, the reaction mixture was concentrated under reduced pressureand the residue was subjected to a silica gel chromatography (eluent:hexane-ethyl acetate=4:1→1:1) to obtain the intended optically activeepoxy compound [I] or [II].

The result is shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________    Asymmetric epoxidation using iodosobenzene as an oxidizing agent                                              Chemical                                                                           Optical                                                                            Optical                                                             Yield                                                                              Yield                                                                              Rotation in                         Substrate           Catalyst                                                                           Temperature                                                                          (%)  (% E.e.)                                                                           CHCl.sub.3                          __________________________________________________________________________     ##STR17##          A B B C D E                                                                        r.t. r.t. -20°C. r.t. r.t. r.t.                                               73 94 82 70 92 72                                                                  63 88 90 67 49 70                                                                  (+) (+) (+) (-) (+ ) (-)             ##STR18##          B B  r.t. -20° C.                                                                  76 70                                                                              86  87                                                                             (-) (-)                              ##STR19##          B B  r.t. -20° C.                                                                  83 77                                                                              87 89                                                                              (-) (-)                             __________________________________________________________________________     r.t.: room temperature                                                   

(2) Reaction Example which uses sodium hypochlorite as an oxidizingagent

To 0.5 ml of dichloromethane was added 0,076 mmol of the compound [V] or[VI], 1.52×10⁻³ mmol of the optically active (salen)manganese complex[III] or [IV], 0.45 ml (adjusted to pH=11.3) of 0.55 M sodiumhypochlorite (co-existence with 0.075 ml of 0.05M sodium phosphate (II))and 1.52×10⁻³ mmol of lutidine N-oxide and stirred for twenty four hoursat 0° C. The mixture was extracted with dichloromethane. The extractedsubstance dried and concentrated under reduced pressure was subjected toa column chromatography (eluate: hexane-ethyl acetate=4:1→1:1) toisolate the intended optically active epoxy compound [I] or [II].

The result is shown in Table 2.

                                      TABLE 2                                     __________________________________________________________________________    Asymmetric epoxidation using sodium hypochlorite as an oxidizing              __________________________________________________________________________    agent                                                                                                         Chemical                                                                           Optical                                                                            Optical                                                             Yield                                                                              Yield                                                                              Rotation in                         Substrate           Catalyst                                                                           Temperature                                                                          (%)  (% E.e.)                                                                           CHCl.sub.3                          __________________________________________________________________________     ##STR20##          B    0° C.                                                                         33   92   (+)                                 __________________________________________________________________________

Reference Example

The asymmetric epoxidation reaction of the compound [V] was conductedunder the same conditions of the Example 4-(1) by using the followingcatalyst F described in Tetrahedron: Asymmetry (vol. 2, pp. 481-494,1991). The result was that only 19% of optical purity was obtained. (seeTable 3).

                                      TABLE 3                                     __________________________________________________________________________    (Reference).                                                                  Asymmetric epoxidation using iodosobenzene as an oxidizing                    __________________________________________________________________________    agent                                                                                                         Chemical                                                                           Optical                                                                            Optical                                                             Yield                                                                              Yield                                                                              Rotation in                         Substrate           Catalyst                                                                           Temperature                                                                          (%)  (% E.e.)                                                                           CHCl.sub.3                          __________________________________________________________________________     ##STR21##          F    r.t.   90   19   (+)                                 __________________________________________________________________________     r.t.: room temperature                                                        Catalyst F                                                                    ##STR22##                                                                    -  (Determination of Optical Purity)                                      

Measured by high performance liquid chromatography using an opticallyactive liquid chromatographic column (Chiralcell OJ, 250 mm×4.6 mm mfd.by Daicel Chemical Industries , Ltd.).

Eluent: hexane- isopropanol=2:1

Flow rate: 0.5 ml/min.

Detected wavelength: 254 nm

What is claimed is:
 1. An optically active manganese complex of theformula: ##STR23## wherein R¹, R², R³, R⁴ and R⁵ are same or differentand represent hydrogen atom or straight chain or branched alkyl grouphaving 1 to 4 carbon atoms , or phenyl group which is unsubstituted orsubstituted by one or more substituents arbitrarily selected from one ormore groups of fluorine atom, chlorine atom, bromine atom, straightchain or branched alkyl group having 1 to 4 carbon atoms and straightchain or branched alkoxyl group having 1 to 4 carbon atoms, Arrepresents phenyl group which is unsubstituted or substituted by one ormore substituents arbitrarily selected from one or more groups offluorine atom, chlorine atom, bromine atom, straight chain or branchedalkyl group having 1 to 4 carbon atoms and straight chain or branchedalkoxyl group having 1 to 4 carbon atoms, and the absolute configurationof the carbon atom shown by asterisks means R or S and X⁻ represents acounter anion.